Cancer can be defined as abnormal growth of tissues characterized by a loss of cellular differentiation. It is caused due to a deregulation of the signaling pathways involved in cell survival, cell proliferation and cell death.
Current treatments for cancer have limited effectiveness and a number of side effects. Cancer therapy currently falls under the following categories including surgery, radiation therapy, chemotherapy, bone marrow transplantation, stem cell transplantation, hormonal therapy, immunotherapy, anti-angiogenic therapy, targeted therapy, gene therapy and others.
Angiogenesis is the process of forming new blood vessels and is critical in many normal and abnormal physiological states. Angiogenesis is normally observed in wound healing, fetal and embryonic development and formation of corpus luteum, endometrium and placenta. However angiogenesis is also the fundamental step in the transition of tumors from a dormant state to a malignant state. In diseases like cancer, the body loses the ability to maintain balanced angiogenesis. New blood vessels feed diseased tissues, destroying normal tissues and sometimes are involved in tumor metastasis. Hence, anti-angiogenic agents are a very promising class of drugs to block or slow the cancer growth.
Vascular Endothelial Growth Factor (VEGF), a signal protein, stimulates the growth of new blood vessels. It is involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). Anti-VEGF therapies are important in the treatment of age-related macular degeneration and in certain cancers such as breast cancer, oesophageal cancer, melanoma, colorectal cancer and tumors of central nervous system.
Protein kinases play important roles in regulating most cellular functions such as proliferation, cell cycle, cell metabolism, survival, apoptosis, DNA damage repair, cell motility and response to the microenvironment. Protein kinases can be divided into broad groups based upon the identity of the amino acid(s) that they target (serine/threonine, tyrosine, lysine, and histidine). There are also dual-specific protein kinases that target both tyrosine and serine/threonine, such as mitogen-activated protein kinases (MAPKs). MAPKs are commonly activated in cancer cells and are known to contribute to tumorigenesis. The protein tyrosine kinases (PTKS) compose a large family of kinases that regulate cell to cell signals involved in growth, differentiation, adhesion, motility, and death. Members of the tyrosine kinase include, but are not limited to, MuSK, JAK2 and ROS. The JAKs are integral in signaling from extracellular cytokines, including the interleukins, interferons as well as numerous hormones. The importance of these kinases in cellular survival is made evident by the fact that the loss of JAKs is often accompanied by immunodeficiency and non-viability in animal models.
The family of serine/threonine kinases includes, but is not limited to, DNA-PK, ALK1, ALK2, CLK1, CLK4 and RIPK2. The DNA-PK is a nuclear serine/threonine protein kinase that is activated upon association with DNA. DNA-PK has been shown to be a crucial component of both the DNA double-strand break (DSB) repair machinery and the V(D)J recombination apparatus. DNA-PK is required for the non-homologous end joining (NHEJ) pathway of DNA repair, which rejoins double-strand breaks. Hence DNA-PK finds use in the treatment of cancers. Another kinase, activin receptor-like kinase 1 (ALK-1) is a type I cell surface receptor for transforming growth factor beta receptor type I (TGF-β1). Mutations in ALK-1 are associated with heredity hemorrhagic telangiectesia (HHT), suggesting a critical role for ALK-1 in the control of blood vessel development or repair (J. Med. Genet., 2003, 40, 494-502). Also, in-vivo experiments on ALK-1 knockout mice provide the evidence of ALK-1 involvement in angiogenesis (Proc. Natl. Acad. Sci. USA, 2000, 97, 2626-2631).
Phosphoinositide 3-kinases (PI3Ks) are attractive therapeutic targets in various diseases, such as autoimmune and inflammatory disorders and cancer.
PI3K mediated signaling pathway plays a very important role in cancer cell survival, cell proliferation, angiogenesis and metastasis. Activation of PI3K results in a disturbance of control of cell growth and survival, and hence this pathway is an attractive target for the development of novel anticancer agents (Nat. Rev. Drug Discov., 2005, 4, 988-1004). Activation of PI3K results in the recruitment and activation of protein kinase B (AKT) onto the membrane, which gets phosphorylated at Serine 473 (Ser-473).
Phosphatidylinositol-3-kinases or phosphoinositol-3-kinase (PI3-kinases or PI3Ks), are a family of lipid kinases that are capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol. The PI3K family is composed of Class I, II and III. The classification is based on primary structure, regulation and in vitro lipid substrate specificity. Class III PI3K enzymes phosphorylate PI (phosphaotidylinositol) alone while, Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate[PI(4)P]. Class I PI3K enzymes phosphorylate PI, PI(4)P and PI 4,5-biphosphate[PI(4,5)P2]. Class I PI3Ks are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism. Class Ia PI3Ks include PI3K p110α, p110β and p110δ subtypes and are generally activated in response to growth factor-stimulation of receptor tyrosine kinases. The regulatory p101 and catalytic p110γ subunits comprise the type Ib PI3K. The subtypes p110α and p110β are expressed in all cells, but p1106 is expressed primarily in leukocytes.
Akt is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration. It is known to positively regulate cell growth (accumulation of cell mass) by activating the mTOR serine threonine kinase. mTOR (mammalian target of rapamycin) serves as a molecular sensor that regulates protein synthesis on the basis of nutrients. mTOR regulates biogenesis by phosphorylating and activating p70S6 kinase (S6K1), which in turn enhances translation of mRNAs that have polypyrimidine tracts. The phosphorylation status of S6K1 is a bonafide read-out of mTOR function. Most tumors have an aberrant PI3K pathway (Nat. Rev. Drug Discov., 2005, 4, 988-1004). Since mTOR lies immediately downstream of PI3K, these tumors also have hyperactive mTOR function. Thus, most of the cancer types will potentially benefit from molecules that target PI3K and mTOR pathways.
Inhibition of PI3K-Akt pathway suppresses coagulation and inflammation (Arteriosclerosis, Thrombosis, and Vascular Biology, 2004, 24, 1963).
SF1126 (Semaphore Inc.) is in phase I clinical trials. SF1126 is a covalent conjugate of LY294002 containing a peptide-based targeting group. In vivo, it gets converted spontaneously at physiologic pH to LY294002 which is a viable version, and as a prodrug, it is able to block PI3K without affecting the normal cells. GDC-0941 (Piramed Ltd. and Genentech Inc.) is a PI3K inhibitor and is in phase I clinical trials. BEZ-235 and BGT-226 (Novartis AG), both in phase I/II clinical trials, inhibit all isoforms of PI3K and also inhibit the kinase activity of mTOR. XL-765 (Exelixis Inc.) is also a dual inhibitor of mTOR and PI3K. The compound is in phase I clinical trials as an oral treatment for solid tumors.
WO2006/122806 describes imidazoquinolines as lipid kinase inhibitors that are used alone or in combination with one or more other pharmaceutically active compounds for the treatment of an inflammatory or obstructive airway disease such as asthma or a proliferative disease such as a tumor disease.